Maintenance hemodialysis for end stage renal disease (ESRD) patients requires a reliable means of repetitive access to large blood vessels that are capable of rendering rapid extracorporeal blood flow to an artificial kidney. Typically an artery and vein are sutured to form a fistulae which enlarges to a point of maturity over several months. Synthetic grafts are also used.
Hemodialysis patients receiving dialysis treatment via native vein arteriovenous fistulae and synthetic grafts typically undergo puncture of skin, subcutaneous tissue, and vascular access with 14-17 gauge needles two to three times weekly. When the procedure is finished and the needles are removed from the skin, many patients bleed from the puncture site for an extended period of time such that the standard treatment involves post-hemodialysis compression at the site for at least 15-20 minutes.
Problems are commonly associated with repeated vascular access, i.e., access to circulation, and include hyperplasia, thrombosis, hematoma, venous stenosis, arterial stenosis, vascular occlusion, infection, and morbidity. Thrombosis, i.e., a blood clot, is the primary cause of access failure responsible for 50% of cases in polytetrafluoroethylene (PTFE) grafts. In those situations where anatomic lesions can be identified, the pathology has been found to be intimal hyperplasia. Other causes of vascular access complications include: venous or arterial stenosis and infection (Mayers 1992, ASAIO J. 38:113-115). These complications with vascular access sites lead to blocking or narrowing of vascular access sites which in turn result in an increased incidence of surgery to repair, replace, or create new vascular access sites. Degradation of the vascular access site also results in a reduction in the delivered dose of dialysis through the use of temporary catheters or reduced blood flow (Hakim and Himmelfarb, 1998, Kidney International, 54:1029-1040). Schwab found that 30% of hemodialysis patients with A-V fistulae, allowed to mature for 60 days, required intervention after about 800 days of hemodialysis therapy, and 80% of hemodialysis patients with A-V grafts required intervention after about 800 days of hemodialysis therapy. After 400 days of hemodialysis therapy, about 18% of A-V fistulae patients and 50% of A-V graft patients required intervention, and after about 200 days 10% of A-V fistulae and 30% of A-V graft patients required intervention (Schwab, 1999, Kidney International, 55:2078-2090).
Hemodialysis vascular access is also a major risk factor for infection and bacteremia, caused mostly by staphylococcal organisms, such as, but not limited to, S. taphylococcus aureus and Enterococcus spp. (Nassar and Ayus, 2001, Kidney International 60:1-13; Tokars et al., 2002, AJIC 30:288-295). These infections and bacteremia lead to complications such as degradation in vascular access sites and surgical replacement of vascular access sites. Other complications can include infectious endocarditis, septic arthritis, epidural abscess, septic pulmonary emboli, and osteomyelitis. Infections and bacteremia can be clinically diagnosed or a leukocyte-labeled indium scan of the vascular access site can be performed to identify infection where clinical manifestation of infection is not apparent or definite. One skilled in the art would know how to perform such scans and identify infections or resulting vascular access complications.
The pathology and risk factors for vascular access complications have been studied. Age, diabetes, the use of synthetic grafts, serum levels of liproprotein(a) (Lp(a))≧57 mg/dL, serum fibronectin, calcification, apolipoprotein(a) serum levels, excessive compression of the vascular access site following hemodialysis or during sleep, turbulent blood flow and reduced blood pressure have been identified as predisposing to access occlusion (Berkoben, 1995, ANNA J. 22:17-24; Butterly, 1994, Adv. Ren Rep. Thpy. 1:163-166; Goldwasser 1994, AJKD 24:785-794; Astor et al., 2002, Kidney International 61:1115-1123). The cause of vascular access complications is suggested to be multifactorial and poorly understood (Goldwasser, 1994, AJKD 24:785-794; Schwab, 1989, Kidney International, 36:707-711; and Windus, 1997, AJKD 29(4):560-564).
Hemodialysis patients also have an increased bleeding tendency due to platelet dysfunction and ineffective platelet-vessel interaction induced by uremia. In hemodialysis patients, the risk of prolonged bleeding is further increased by systematic anticoagulation resulting from the continuous infusion of heparin during the dialysis procedure (Di Minno et al., 1985, Am. J. Med. 79:552-559). Many of these patients have a high incidence of cardiovascular risk factors. A retrospective study done by the Department of Anesthesiology of the Mayo Clinic reported that for all the patients requiring creation of an A-V fistula in the years 1986 to 1991, 92% suffered from hypertension, 86% from coronary artery disease and 42% from a previous myocardial infarction (Solomonson, 1994, Anesth. Analg. 79:694-700). Most of this group of patients must be on prophylactic anticoagulation therapy with aspirin or warfarin. Further, thiazide diuretics, which are commonly used to treat hypertension or congestive heart failure, impair megakaryocyte production and can produce mild thrombocytopenia which may persist for several months after the drug is discontinued (Harrison's Principles of Internal Medicine 13th Ed. 1994, p. 1799).
Hemostasis, i.e., the stopping or cessation of bleeding, is often compromised in hemodialysis patients. The abnormal hemostasis associated with ESRD patients is most apparent in the prolonged post treatment bleeding. Traditionally, when the cannulation needles are removed at the end of treatment, many hemodialysis patients require long compression times at the site of removal to stop bleeding. Hemostasis is typically obtained by 15-20 minutes of manual compression (Schwab, 1994, Kidney International 36:707-711). Vaziri reported that in the population of heparinizied ESDR patients studied the mean bleeding time was about 7-9 minutes following hemodialysis which was reduced to about 3.2-3.3 minutes with the topical administration of bovine thrombin to the site where the hemodialysis needles are removed (Varizi et al., 1978, Journal of Dialysis, 2:393-398; and Varizi, 1979, Nephron 24:254-256).
Several compositions that can act as hemostatic agents and typically include collagen or fibrin are known (Falstrom et al., 1997, Catheterization and Cardiovasular Diagnosis 41:79-84; Hoekstra et al., 1998, Biomaterials. 19:1467-1471; Prior et al., 2000, Journal of Biomedical Materials Research. 53(3):252-257). U.S. Pat. No. 4,394,373, for example, discloses compositions that act as coagulants and may be used to promote clotting of a wound by placing the compositions in contact with the wound where the composition comprises liquid or powder chitosan. U.S. Pat. No. 5,510,102, for example, discloses compositions that act as coagulants and may be used to promote clotting of a wound by placing the compositions in contact with the wound where the composition comprises platelet rich plasma plus a biocompatible polymer that is a hemostatic agent such as alginate. The compositions of U.S. Pat. Nos. 4,394,373 and 5,510,102 are either applied directly to the wound surface, in the case of treatment of a superficial wound or in the case of a puncture in an artery left by a needle or catheter.
Preserving access function and long-term vascular access is essential for the care of dialysis patients, particularly now that high-efficiency dialysis places even more demands on access function, and with increasing numbers of older, sicker patients entering the ESRD program with limited access sites. Vascular access complications remain the single greatest cause of morbidity and account for approximately one third of all admissions and hospitalization days in the hemodialysis population (Spergel, 1997, Neph. News and Issues. 3:26-27, 35). An average 1.2-2.8 surgical procedures per patient are performed each year to repair or replace the vascular access site (Brothers et al., 1996, J. Sur. Research 60:312-316; Harland, 1994, Adv. Ren. Rep Therapy 1:99-106). As much as $1 billion annually is spent on placement and maintenance of vascular access (Spergel, 1997; Hakim and Himmelfarb, 1998, Kidney International, 54:1029-1040).
High rates of vascular access complications in the hemodialysis population coupled with the increased use of high flux dialyzers, which require higher blood flow, draw attention to the need for new methods for maintaining blood flow through vascular access sites (Hakim and Himmelfarb, 1998, Kidney International, 54:1029-1040).
The patents and published articles referenced in this section are incorporated by reference herein in their entirety.